Medical experts at Cornell University say a unique combination of medications may be able to help women with breast cancer get pregnant without increasing the risk of their cancer coming back.
The combinational approach is described in an ongoing study whose initial findings were published online at the website of the Journal of Clinical Oncology April 11.1 However, in an editorial accompanying the study, two doctors claim the research was too small and the follow-up of each patient too brief to make any definite conclusions about the safety of the approach.2
The Estrogen Link
Studies have shown that combinations of fertility drugs used in in-vitro fertilization (IVF) procedures promote the production of estrogen,3 and it's known that estrogen increases the risk of breast cancer.4 "Laboratory studies have shown that breast cancer cells can gain more invasive behavior with estrogen exposure," said lead investigator Kutluk Oktay, MD, in an interview.
But for ethical reasons, there have been no clinical studies with patients to determine the effects of standard IVF therapy on the risk of breast cancer recurrence, said Oktay, who is director of the Fertility Preservation Program at the Center for Reproductive Medicine and Infertility at New York Presbyterian Hospital/Weill Cornell Medical Center in New York.
Alternative Tested for Breast Cancer Patients
In an attempt to avoid the risk of recurrence, Oktay's team used two alternative ovulation induction protocols that included breast cancer therapies: tamoxifen (Nolvadex) or letrozole (Femara), in combination with follicle stimulating hormone (FSH), used in standard ovulation induction protocols to stimulate the production of eggs. One group of patients in the study underwent IVF and the second group chose not to.
They then divided the women into three groups; the first received tamoxifen alone, the second group was given tamoxifen in combination with low-dose FSH, and the third group received letrozole combined with low-dose FSH. A total of 33 ovarian stimulation cycles using these approaches were performed.
"After IVF, all resultant embryos were cryopreserved to preserve fertility," Oktay's team wrote. "Recurrence rates were compared with controls who elected not to undergo IVF."
Compared with the group using tamoxifen alone, those given tamoxifen/FSH or letrozole/FSH had greater numbers of mature follicles for egg retrieval. The latter two groups had more mature eggs collected and more embryos fertilized, in addition.
But those taking letrozole and FSH had the best outcomes. There was between 1 and 2 mature eggs, on average, collected in the group taking tamoxifen alone, compared to more than five in the group taking tamoxifen combined with FSH, and more than eight in the group given letrozole and FSH. Likewise, while just over one embryo, on average, was fertilized in the tamoxifen alone group, there were nearly four embryos produced in the group taking tamoxifen and FSH, and over five embryos in the letrozole/FSH group, on average. "Even though statistically similar, the letrozole protocol yielded an extra embryo, and in our extended study, resulted in significantly larger numbers of eggs with much less estradiol [estrogen] production," Oktay explained.
One woman returned during the study to have one of her embryos thawed and transferred to a surrogate, but the pregnancy ended in miscarriage. Since this paper's publication, another woman, who was in the letrozole group, returned for embryo transfer and successfully became pregnant, Oktay stated. She has since given birth to a healthy baby.
Patient Follow-up
The study investigators followed each patient for an average of 554 days (about 1.5 years). When examining the incidence of cancer recurrence, the study group found that it was the same between those who underwent IVF and those who did not. Recurrence occurred in three women who underwent IVF compared to three women who elected not to have it performed. Peak estrogen levels were lower in the groups given combination therapies before IVF compared with those given tamoxifen alone, as well.
”The combination of low-dose FSH with tamoxifen or letrozole results in higher embryo yield compared with [tamoxifen alone]," wrote Oktay and his colleagues. "Recurrence rates do not seem to be increased, but the letrozole protocol may be preferred because it results in lower peak estrogen levels."
Study Reaction
In an editorial related to the study, Ann Partridge, MD, and Eric Winer, MD, both of the Dana Farber Cancer Institute, wrote that while the findings were valuable, there were some reservations about the study as a whole. Due to the small numbers of patients involved, and the relatively short period of follow-up exams, it is too early to draw definitive conclusions about using these alternative treatment plans for women with breast cancer undergoing IVF.
"Given the low pregnancy rates reported in the study by Oktay [and others], the true benefit of these strategies has yet to be determined," they wrote.
But Oktay says the editorial "took an extremely cautious approach." Since its publication, "we have doubled the number of the patients and the study is still going on. We still have not seen a single patient with recurrence in the letrozole group, and a similar ratio [of recurrence] in the tamoxifen groups (10%) compared to controls."
Even though the study is still ongoing, "if there was a drastic negative effect, we would have seen it by now," Oktay said. "This approach also lowers the cost of IVF as the patients will need half the dose of FSH needed with standard IVF."
1. Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 2005 Apr 11;[Epub ahead of print].
2. Partridge AH, Winer EP. Fertility after breast cancer: questions abound. J Clin Oncol 2005 Apr 11;[Epub ahead of print].
3. Siegelmann-Danieli N, Tamir A, Zohar H et al. Breast cancer in women with recent exposure to fertility medications is associated with poor prognostic features. Ann Surg Oncol 2003 Nov;10(9):1031-8.
4. Platet N, Cathiard AM, Gleizes M, Garcia M. Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol 2004 Jul;51(1):55-67.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
